What is Targeted Alpha-emitter Therapy?

Regular PRRT which is authorised for use now, i.e. Lutathera/Lu177 is a beta therapy.  Targeted Alpha Therapy is based on the coupling of alpha particle emitting radioisotopes to tumour selective carrier molecules, such as monoclonal antibodies or peptides. These molecules have the ability to selectively target tumour cells even if they are spread throughout the body. They recognize the targeted cancer cells through antigens that are expressed on the cell surface and can bind selectively to these cells, similar a key fitting into a lock. In targeted alpha therapy these carrier molecules serve as vehicles to transport the radioisotopes to the cancer cells. This is called the “magic bullet” approach. Radioisotopes that emit alpha particles seem particularly promising to selectively destroy cancer cells. Alpha particles have a high energy in the range of 5-9 MeV and at the same time a very short path length in human tissue below 0.1 mm, corresponding to less than 10 cell diameters. Consequently, the use of alpha emitters allows the specific targeting and killing of individual malignant cells, while minimizing the toxicity to surrounding healthy tissue. Extracted from EU Science Hub

According to the clinical trials document, this drug addresses an unmet need in the field of peptide receptor radionuclide therapy (PRRT) for NETs. Substitution of an alpha emitter (e.g. ²¹²Pb) for the beta emitters currently being used (i.e., 177Lu or 90Y) will provide significantly higher Linear Energy Transfer (LET) and a shorter path length. Higher LET particles should cause more tumor cell death. Shorter path length should result in less collateral damage of the normal tissue and therefore less side effects for subjects receiving the drug.

What is the difference between ‘regular’ PRRT and the Alpha version?

From the scant ‘patient understandable‘ information currently available, it would appear that alpha therapy has the potential to be more targeted and less toxic than beta PRRT – to me that seems like it would be able to target smaller tumours.

The main effort for NETs is based on the use of two TAT radionuclides – ²²⁵Actinium and ²¹²Pb

Where can I get alpha-emitter PRRT

A lot of people ask me this.  Clearly this is a discussion to be had with your doctors.  Just because alpha-emitter has the above advantages does not mean it (or any PRRT type) is suitable for you.

It’s still in development but clinical trials are starting to become available, mainly in US and Europe (on a clinical trial basis), but there could be some access in South Africa and India.

The main clinical trials can be found here:

AC225 –click here

Pb212 – click here

South Africa.  Anecdotally from a trusted source, AC225 is available “off trial” from Dr. Mike Sathekge at Head of Dept: Nuclear Medicine
University of Pretoria / Steve Biko Academic Hospital

India – see section about India below.

But see clinical trials summary below.

Clinical trials – 212Pb-AR-RMX

Update 3 Jan 2022. Radiomedix and Orano Med Announce the Initiation of the Phase II Multi-Center Clinical Trial of Alphamedix™ for Targeted Alpha-Emitter Therapy of Neuroendocrine Cancers

Phase 2 trial – click here or on the picture above

Background reading in addition to the Phase 2 trial above:  Phase 1 trial information

In 2018, RadioMedix Inc. and Orano Med initiated the Phase 1 trial for AlphaMedix^TM in patients with somatostatin receptor (SSTR) positive Neuroendocrine Tumors (NETs) – an NIH supported trial.

AlphaMedix^TM is composed of a somatostatin analogue radiolabeled with ²¹²Pb, an isotope used for Targeted Alpha-emitter Therapy (TAT).  This open-label, dose escalation study’s objective is to determine safety, bio-distribution, and preliminary effectiveness of 212 Pb-AR-RMX in adult patients with differentiated (sic) NETs. “Targeted Alpha-emitter Therapy (TAT) is the wave of the future in nuclear oncology and has a tremendous potential to treat patients with NET and overcome some of the limitations of current Peptide Receptor Radionuclide Therapy (PRRT)” said Dr. Ebrahim S. Delpassand, Chairman and CEO of RadioMedix, sponsor of the trial. They further announced on 21 Feb 2018 that the first patients had undergone some treatment.

Related articles:

Phase 1 Clinical Trial Document – Phase 1 Study of AlphaMedix™ in Adult Subjects With SSTR (+) NET – click here

Phase 2 document – Targeted Alpha-emitter Therapy of PRRT Naive Neuroendocrine Tumor Patients (ALPHAMEDIX02) click here

Ornamed Website – click here

RadioMedix Inc Website – click here

Some advance info on the data from the Phase 1 trial results (quote from Dr Strosberg)

“Some exciting data on peptide receptor radionuclide therapy have been released with regard to the alpha particle–emitting isotope 212Pb–DOTATATE; this [treatment] was associated with exceptionally high response rates with the maximum-tolerated dose, which was discovered in the phase 1 study. Alpha emission is completely different from beta-emitting [radionuclide therapy], such as lutetium-177 (Lutathera)or yttrium-90; it delivers a much higher energy over a much shorter particle length. Although development may take more than a few years, I believe this [approach] has the potential to improve the therapeutic index that we are currently seeing with lutetium-177” Read the quote reference here.

This has been taken from the Radiomedix website:

This summary was presented at ASCO 2021 as an abstract:

DOI: 10.1200/JCO.2021.39.15_suppl.4117 Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021) 4117-4117.

Conclusions: This F-I-H clinical study of AlphaMedix shows that PRRT with ²¹²Pb is feasible, well tolerated, and provides substantial reduction in tumor burden to patients with unresectable, metastatic SSTR-expressing NETs. Dramatic improvement in tumor burden and a positive impact on quality of life were seen in all of the PRRT naïve subjects who AlphaMedix at the highest dose tested.

Clinical trials – 225Ac

1.  NEW Nov 2025 – Ariceum Therapeutics begins patient dosing in in SANTANA-225 phase 1/2 trial of 225Ac-SSO110 to treat patients with somatostatin receptor positive ES-SCLC and Merkle cell carcinoma. Click here

2. NEW Sep 2022.  Clinical Trial: Phase 1b/3 Targeted Alpha-Emitter PRRT RYZ101 (Ac225) – Ronny Allan – Living with Neuroendocrine Cancer

3. There seems to be quite a bit of use in India, not much is known if the Indian Drug Approval authorities have authorised it or it’s being used on a clinical trial basis (see more below).  Check this German study on the best and safest dosage over a 5 year period. Dosing ²²⁵Ac-DOTATOC in patients with somatostatin-receptor-positive solid tumours: 5-year follow-up of haematological and renal toxicity.  Click here to read

AC225 Alpha PRRT in India – CNETS India website

Two nuclear medicine centres in India have started Alpha PRRT for NET patients.  World over, many clinical trials have established the benefit of PRRT for metastatic NETs. Alpha PRRT uses the more powerful alpha particle emitting agents, Actinium 225 or Bismuth 213, in place of Lutetium 177 or Yttrium 90, which are the commonly used beta emitters for PRRT, to target the somatostatin receptors expressed by the tumour cells. According to CNETS India, Alpha PRRT holds higher energy leading to higher efficacy and lower toxicity to normal tissues and hence lesser side effects as compared to the currently available Lu177 based PRRT. Currently Alpha PRRT is already available at two ‘super specialty’ hospitals in Delhi and Bengaluru in North and South India, respectively.

Targeted Alpha Theranostics

Read about the involvement of Viewpoint Molecular Targeting (VMT) who are involved in a theranostic approach using TAT.  Presumably working with alongside Radiomedix 212Pb approach.  Read more here:

19th July 2023 Alpha-emitter Clinical Trials Summary 

Just in – a summary of progress to date including a list of alpha-emitter clinical trials, not all NET.

Jang, A.; Kendi, A.T.; Johnson, G.B.; Halfdanarson, T.R.; Sartor, O. Targeted Alpha-Particle Therapy: A Review of Current Trials. Int. J. Mol. Sci. 2023, 24, 11626.

Click here – IJMS | Free Full-Text | Targeted Alpha-Particle Therapy: A Review of Current Trials (mdpi.com)

Update 27th July 2022

This real-world study from India using 225Ac and Capecitabine chemotherapy is interesting.  Read more by clicking here or on the photo below:

Update 15th June 2022

SNNMI Abstract of the Year: Targeted Radionuclide Treatment Achieves High Response Rate, Minimal Toxicities for Advanced-Stage Neuroendocrine Tumours

June 14, 2022

Reston, VA — A targeted radionuclide alpha therapy, ²²⁵Ac-DOTATATE, has been shown to have long-term anti-tumour effects in patients with advanced-stage gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Results from the Phase II study showed promising survival rates, high response rates and an acceptable toxicity profile, making ²²⁵Ac-DOTATATE a potential treatment option for patients who have exhausted other forms of therapy. This research was presented at the Society of Nuclear Medicine and Molecular Imaging 2022 Annual Meeting and was selected as the meeting’s Abstract of the Year.

Each year, SNMMI chooses an abstract that best exemplifies the most promising advances in the field of nuclear medicine and molecular imaging. This year, the SNMMI Henry N. Wagner, Jr., Abstract of the Year was chosen from more than 1,000 abstracts submitted to the meeting and voted on by reviewers and the society leadership.

GEP-NETs are rare malignancies that arise from neuroendocrine cells and can be present all along the gastrointestinal tract. While patients with early-stage GEP-NETs can undergo surgery to cure the disease, the majority of patients are diagnosed with metastatic disease, making systemic treatment—such as targeted radionuclide therapy—their only option. ¹⁷⁷Lu-DOTATATE has been proven to be an effective targeted beta radionuclide therapy; little evidence, however, is available on targeted alpha radionuclide therapies for GEP-NETs.

In the study, researchers aimed to evaluate the long-term efficacy, survival outcomes, and safety of the targeted radionuclide alpha therapy ²²⁵Ac-DOTATATE in GEP-NET patients. Eighty-three GEP-NET patients (including 56 patients with prior ¹⁷⁷Lu-DOTATATE treatment and 27 ¹⁷⁷Lu-DOTATATE-naïve patients) received systemic treatment with ²²⁵Ac-DOTATATE intravenously at eight weekly intervals.

Hematologic, kidney and liver function tests were performed before and after each cycle. Tumours were measured using RECIST 1.1 criteria at baseline and after two cycle intervals. Overall survival, radiographic progression-free survival, objective tumour response, and treatment-related adverse events were assessed.

After the treatment course, two patients (2.7 percent) had complete response, 32 (43.2 percent) had a partial response, 25 (34 percent) had stable disease, and 15 (20 percent) had progressive disease. Minimal toxicities were noted after treatment with ²²⁵Ac-DOTATATE.

“²²⁵Ac-DOTATATE is a promising therapy option that adds a new dimension to the treatment of end-stage GEP-NETs, especially for patients who have tried all other standard therapy options,” said Chandrasekhar S. Bal, MD, DNB, DSc (HC), FAMS, FNASc, FASc, professor and head of the Department of Nuclear Medicine and PET at the All India Institute of Medical Science in New Delhi, India. “These results warrant a Phase III randomized control trial to assess the true efficacy of ²²⁵Ac-DOTATATE versus ¹⁷⁷Lu-DOTATATE.”

“The results from this study not only emphasized the promise and success of targeted alpha therapies but also reflected growing global interest in these life-extending treatments,” said Heather Jacene, MD, SNMMI Scientific Program Committee chair. “We look forward to further research on this topic in the future.”

Source.  SNMMI 2022 conference

Disclaimer

I am not a doctor or any form of medical professional, practitioner or counsellor. None of the information on my website, or linked to my website(s), or conveyed by me on any social media or presentation, should be interpreted as medical advice given or advised by me.

Neither should any post or comment made by a follower or member of my private group be assumed to be medical advice, even if that person is a healthcare professional. Some content may be generated by AI which can sometimes be misinterpreted.  Please check any references attached.

Please also note that mention of a clinical service, trial/study or therapy does not constitute an endorsement of that service, trial/study or therapy by Ronny Allan, the information is provided for education and awareness purposes and/or related to Ronny Allan’s own patient experience. This element of the disclaimer includes any complementary medicine, non-prescription over the counter drugs and supplements such as vitamins and minerals.

General Clinical Trials Disclaimer

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided in the clinical trials document. It’s very important to check the trial inclusion and exclusion criteria before making any contact.  If you need questions, the articles here is very useful Questions to Ask About Clinical Trials | Cancer.Net

The inclusion of any trial within this blog should not be taken as a recommendation by Ronny Allan.

Finally

Whenever I post about a trial or study, some people get excited without understanding that these new treatments and capabilities can very often take years to come to fruition and it’s also possible that clinical trials can be halted, or that national approval agencies will not approve the final product.  Plus, not everyone will be eligible, so always check the exclusion and inclusion criteria in the relevant clinical trials document.   Please bear that in mind when reading studies/clinical trials posted on RonnyAllan.NET

Click here to enter Ronny’s Clinical Trials Archive

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